Pharmaceutical composition comprising pyridone derivatives

ABSTRACT

A pyridone derivative compound and a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof, and a preventive or therapeutic pharmaceutical composition for cognitive disorders that includes the pyridone derivative compound or a pharmaceutically acceptable salt, isomer, solvate or hydrate thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/581,482, filed 23 Dec. 2014, which is a continuation of U.S.application Ser. No. 13/980,821, filed 19 Jul. 2013, which is a nationalphase application of PCT Application No. PCT/KR2012/000652, filed onJan. 30, 2012, which claims the benefit and priority to Korean PatentApplication No. 10-2011-0008962, filed Jan. 28, 2011. The entiredisclosures of the applications identified in this paragraph areincorporated herein by references.

FIELD

The present invention provides an azabicycloalkane-substituted pyridonederivative compound as an agonist or partial agonist of a 7-nicotinicacetylcholine receptor (nAChR), and a pharmaceutically acceptable salt,isomer, solvate, or hydrate thereof.

BACKGROUND ART

Nicotinic acetylcholine receptors (nAChR), which are of a ligand-gatedion channel family, are prevalent in the central nervous system (CNS)and peripheral nervous system (PNS), and are involved in a variety ofphysiological functions. These receptors serve as important factors incontrolling CNS's physiological functions via controlling the release ofa variety of neurotransmitters, such as acetylcholine, norepinephrine,dopamine, serotonin, and gamma-aminobutyric acid (GABA). Therefore, withthe control of such neurotransmitters and the cellular signal transfersystem, AChR may be used in treating diseases associated with cognitivefunction, learning and memory, neurodegeneration, pain and inflammation,neuropsychosis and mood disorder, and compulsive and addictivebehaviors, controlling and treating inflammation or inflammatorydiseases, and in relieving pains.

Diverse nAChR subtypes are present in the CNS and PNS. Typically, nAChRare ionic channels able to selectively transmit diverse cations withfive monomers surrounding a central ion conducting pore of the ionicchannel. In humans, at least 12 monomers, α2˜α10, and β2˜β4 areexpressed, where these monomers form diverse homomeric or heteromericcomplexes through combination with each other. Heteromeric α4β2 nAChRwith high binding affinity to nicotin and homomeric α7 nAChR with lowaffinity to nicotin are known to be main expressions in the CNS [GottiC, Zoli M, Clementi F (2006) Trends in Pharmacol. Sci. 27; 482-491].

Nicotinic α7 receptors, which are expressed in the cerebral cortex andhippocampus that are responsible for brain's cognitive and sensoryfunctions are found both in presynaptic and postsynaptic terminals, andthus have been suggested as a significant factor in synaptic pass[Burghaus L, Schutz U, Krempel U, de Vos R A I, Jansen Steur E N H,Wevers A, Lindstrom J, Schroder H (2000), Mol. Brain Res. 76: 385-388;Banerjee C, Nyengaard R J, Wevers A, de Vos R A I, Jansen Steur E N H,Lindstrom J, Pilz K, Nowacki S, Bloch W, Schroder H (2000), Neurobiol.Disease, 7; 666-672]. Nicotinic α7 receptors are inherently highlypermeable to calcium ions, and thus have been proposed as a significantfactor in diverse calcium-dependent neurotransmission systems [OshikawaJ, Toya Y, Fujita T, Egawa M, Kawabe J, Umemura S, Ishikawa Y (2003) Am.J. Physiol. Cell Physiol. 285; 567-574; Marrero M B, Bencherif M (2009)Brain Res. 1256; 1-7; Ospina J A, Broide R S, Acevedo D, Robertson R T,Leslie F M (1998) J. Neurochem. 70; 1061-1068].

Since nicotinic acetylcholine receptors are involved in the control ofvarious cerebral functions, including cognitive function andattentiveness, substances that are able to directly or indirectlyactivate such nicotinic acetylcholine receptors are expected to beultimately beneficial in relieving cognitive impairments, such asAlzheimer type dementia, schizophrenia associated cognitive disorders,and attention deficit such as attention deficit hyperactivity disorder(ADHD) [Levin E D, McClernon F J, Rezvani A H (2006) Psychopharmacology184; 523-539].

DETAILED DESCRIPTION OF THE INVENTION Technical Problem

The present invention provides an azabicycloalkane-substituted pyridonederivative compound as an agonist or partial agonist of a 7-nicotinicacetylcholine receptor (nAChR), and a pharmaceutically acceptable salt,isomer, solvate, or hydrate thereof.

Technical Solution

According to aspects of the present invention, there are provided apyridine derivative compound represented by Formula I below, and apharmaceutically acceptable salt, isomer, solvate, or hydrate thereof,wherein, in Formula I, A is a C1-C10 heteroaryl group substitutable withat least one selected from the group consisting of a halo group, a C1-C6alkyl group, a C3-C7 cycloalkyl group, a C6-C12 aralky group, a C1-C6alkoxy group, and a C6-C12 aryl group; and B is O or NH.

In some embodiments, B may be NH.

The term “heteroaryl group” used herein refers to a system with at leastone aromatic ring that includes at least one heteroatom selected fromamong N, O and S, and of which the rest of the rings is carbon, and isalso taken to include a condensed ring (bicyclic heteroaryl). In someembodiments, the C1-C10 heteroaryl group may be selected from the groupconsisting of thiazolyl, benzothiazolyl, pyridyl, isoxazolyl,isoquinolyl, quinolyl, benzothiadiazole, thiadiazoly, pyrazolyl, andpyrazinyl.

In some embodiments the aralkyl group and the aryl group may besubstituted by other halo or alkyl groups.

In some embodiments, the pyridone derivative compound of Formula I maybe prepared from any known compound or any compound readily obtainabletherefrom by one of ordinary skill in the art. Therefore, the followingdescriptions associated with methods of preparing the pyridonederivative compound are provided only for illustrative purposes, and arenot intended to limit the scope of the present invention. For example,the order of unit operations may be changed if needed.

In the scheme illustrated above, R may be a heteroaryl group. In ageneral synthesis method illustrated in the above scheme, aftersynthesis of an intermediate 2 from a coumarilic acid 1 as a startingmaterial, the intermediate 2 may react with an amino heteroaryl compound(R—NH₂) and dimethylformamide (DMF) at about 150° C. to obtain a6-pyridone compound 3, which may be then hydrolyzed into6-pyridone-3-carboxyl acid 4, and then a final compound 5 may beobtained via introduction of quinuclidine.

In the scheme illustrated above, R may be a heteroaryl group. Aftersynthesis of 6-oxo-3-carbonylchloride (6) from 6-pyridone-3-carboxylicacid (4), a final compound (7) may be obtained via introduction ofquinuclidinol.

Examples of the pyridine derivative are the compounds represented byFormula I, pharmaceutically acceptable salts, such as additional acid orbase salts, and any stereochemical isomer thereof, wherein these saltsare not specifically limited, and may be any salt that is able to retainactivity of a parent compound thereof in a target subject and does notcause any undesirable effect. Examples of these salts are both inorganicand organic salts, such as acetic acid, nitric acid, aspartic acid,sulfonic acid, sulfuric acid, maleic acid, glutamic acid, formic acid,succinic acid, phosphoric acid, phthalic acid, tannic acid, tartaricacid, hydrobromic acid, propionic acid, benzenesulfonic acid, benzoicacid, stearic acid, cresylic acid, lactic acid, bicarbonic acid,bisulfuric acid, bitartaric acid, oxalic acid, butylic acid, calciumedatate, camsylic acid, carbonic acid, chlorobenzoic acid, citric acid,edetic acid, toluenesulfonic acid, edicylinic acid, ecylinic acid,fumaric acid, gluceptic acid, pamoic acid, gluconic acid,glycollarsanylic acid, methyl nitrate, polygalactronic acid,hexyllisorcynonic acid, malonic acid, hydrobamic acid, hydrochlorinicacid, hydroiodic acid, hydroxynaphtholic acid, isethionic acid,lactobionic acid, mandelic acid, estolinic acid, mucic acid, muconicacid, p-nitromethanesulfonic acid, hexamic acid, phantothenic acid,monohydrogen phosphoric acid, dihydrogen phosphoric acid, salicylicacid, sulfamine acid, sulfanilic acid, methanesulfonic acid, andtheoclic acid. Examples of a basic salt are an ammonium salt, a salt ofan alkali or alkali earth metal such as lithium, sodium, potassium,magnesium, or calcium, a salt containing an organic base such asbenzathine, N-methyl-D-glucamine, or hydrabamine, and a salt containingan amino acid such as arginine or lysine. These salts may be convertedinto a free form by treatment with appropriate acid or base. The term“additional salt” may be construded as including solvates obtainablefrom any of the compounds of Formula I and salts thereof. Examples ofthese solvates are hydrates and alcoholates.

In some embodiments, stereochemical isomers of the pyridone derivativecompound may be any compounds derived from the compounds represented byFormula I. Unless otherwise mentioned or indicated, the chemicaldesignation of a compound encompasses a mixture of any possiblestereochemically isomeric forms which the compound may possess, whereinthe mixture may contain any diastereomers and/or enantiomers of thebasic molecular structure of the compound. In particular, thestereocenter may be in either R or S-configuration, a substituent ofdivalent cyclic (partially) saturated radical may be in either the cis-or trans-configuration. A compound with a double bond may have either Eor Z-stereochemistry in the double bond. Any stereochemical isomer ofthe compound of Formula I or Formula II also falls within the scope ofthe present disclosure.

In some embodiments, the pyridine derivative compound may be selectedfrom the group consisting ofN-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-thiazolyl)-3-pyridinecarboxamide,

-   N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-6-oxo-1-(2-thiazolyl)-3-pyridinecarboxamide,-   N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-oxo-1-(2-thiazolyl)-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-pyridinyl)-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(3-pyridinyl)-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-chloro-2-pyridinyl)-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-phenyl-2-pyridine-1-yl)-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(3-isoxazolyl)-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(3-phenyl-5-isoxazolyl)-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-methyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,-   N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-methyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,-   N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-methyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-ethyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,-   N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-ethyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,-   N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-ethyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-propyl-2-thiazolyl)-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-propan-2-yl-2-thiazolyl)-3-pyridinecarboxamide,-   N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-6-oxo-1-(5-propan-2-yl-2-thiazolyl)-3-pyridinecarboxamide,-   N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-oxo-1-(5-propan-2-yl-2-thiazolyl)-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-tert-butyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,-   N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl)]-1-(5-tert-butyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,-   N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl)]-1-(5-tert-butyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-cyclopentyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-cyclohexyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-phenyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-chloro-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,-   N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-chloro-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,-   N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-chloro-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-[5-(phenylmethyl)-2-thiazolyl]-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-methyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-(4-chlorophenyl)-2-thiazolyl]-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4,5-dimethyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(1,3-benzothiazole-2-yl)-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-methoxy-1,3-benzothiazole-2-yl)-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5,6-dimethyl-1,3-benzothiazole-2-yl)-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2,1,3-benzothiadiazole-4-yl)-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(1,3-benzothiazole-6-yl)-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-methyl-2-phenyl-3-pyrazolyl)-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(1-isoquinolinyl)-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-isoquinolinyl)-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-quinolinyl)-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-methyl-1,3,4-thiadiazole-2-yl)-6-oxo-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-phenyl-1,3,4-thiadiazole-2-yl)-3-pyridinecarboxamide,-   N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-pyrazinyl)-3-pyridinecarboxamide,-   (1-azabicyclo[2.2.2]octan-3-yl)-1-(5-methyl-1,3-thiazole-2-yl)-6-oxo-3-pyridinecarboxylate,    and-   (1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-propan-2-yl-1,3-thiazole-2-yl)-3-pyridinecarboxylate.

In some embodiments, the pyridine derivative compound may be an agonistor partial agonist of an α7 nicotinic acetylcholine receptor.

The term “agonist” used herein is understood to be given its broadestmeaning, i.e, as any molecule that partially or entirely activate atleast one biological activity of a target material (for example, α7nicotinic acetylcholine receptor). For example, the term “agonist”compound refers to a compound that increase or induce the biologicalactivity of a protein (for example, the α7 nicotinic acetylcholinereceptor c-Met) to which the agonist compound binds. For example, thepyridine derivative compound may specifically bind to the extracellulardomain of the α7 nicotinic acetylcholine receptor to induceintracellular signal transmission, proving efficacy in prevention ortreatment of cognitive impairments and in neurological recovery.

Nicotinic α7 receptors are known to be significant in the improvement ofcognitive functions in, for example, learning, memory and attention. Forexample, nicotinic α7 receptors are associated with mild cognitionimpairment, Alzheimer's disease, age-associated and other cognitiveimpairments, neuropsychiatric cognitive disorder, attention deficitdisorder, attention deficit hyperactivity disorder (ADHD), dementiacaused by injection or metabolic disorder, Lewy body dementia,convulsions such as epilepsy, multiple cerebral infarcts, mood disorder,compulsive and addictive behaviors, inflammatory disease, and diseasesand conditions associated with the control of pain caused from thesedisorders. The activity of the nicotinic α7 receptor may be changed orregulated by administration of α7 receptor ligands of which non-limitingexamples are antagonists, agonists, partial agonists, and inverseagonists. α7 receptor ligands are usable in treatment and prevention ofthese various types of cognitive impairments and other conditions anddiseases, and agonists and partial agonists thereof are known to improvecognitive functions and attention in rodents, non-human primates, andhumans [Gotti C and Clementi F (2004) Prog. Neurobiol. 74; 363-396;Jones H E, Garrett B E, Griffiths, R R (1999) J. Pharmacol. Exp. Ther.288; 188-197; Castner S A, Smagin G N, Piser T M, Wang Y, Smith J S,Christian E P, Mrzljak L, Williams G V (2011) Biol. Psychiatry 69;12-18; Wallace T L, Callahan P M, Tehim A, Bertrand D, Tombaugh G, WangS, Xie W, Rowe W B, Ong V, Graham E, Terry A V Jr, Rodefer J S, HerbertB, Murray M, Porter R, Santarelli L, Lowe D A. (2011) J. Pharmacol. Exp.Ther. 336; 242-253; Bitner R S, Bunnelle W H, Decker M W, Drescher K U,Kohlhaas K L, Markosyan S, Marsh K C, Nikkei A L, Browman K, Radek R,Anderson D J, Buccafusco J, Gopalakrishnan M. (2010) J. Pharmacol. Exp.Ther. 334; 875-886; Woodruff-Pak, D S, Santos I S (2000) Behav. BrainRes. 113; 11-19; Spinelli S, Ballard T, Feldon J, Higgins G A, Pryce C R(2006) Neuropharmacology 51; 238-250].

According to another aspect of the present invention, there is provideda pharmaceutical composition for preventing or treating cognitiveimpairment that includes the above-described pyridone derivativecompound, or a pharmaceutically acceptable salt, isomer, solvate orhydrate thereof in a therapeutically effective amount; and apharmaceutically acceptable carrier.

In some embodiments, the cognitive impairment may be selected from thegroup consisting of pre-senile dementia, early onset Alzheimer'sdisease, senile dementia, Alzheimer type dementia, Lewy corpuscledementia, micro-infarct dementia, AIDS-related dementia, HIV-dementia,dementia associated with Lewy bodies, Down's syndrome associateddementia, Pick's disease, mild cognitive impairment, age associatedmemory impairment, recent short-term memory impairment, age-associatedcognitive disorder, drug-associated cognitive disorder, immunodeficiencysyndrome-associated cognitive disorder, vascular disease-associatedcognitive impairment, schizophrenia, attention deficit disorder,attention deficit hyperactivity disorder (ADHD), and learning deficitdisorder. The pharmaceutical composition is neuroprotective in terms ofprevention or treatment of, for example, Alzheimer's disease,Parkinson's disease, amyotrophic lateral sclerosis (ALS), orHuntington's disease.

The term “cognitive disorder” used therein refers to withdrawals in awide range of cognitive functions or cognitive domains in animals, forexample, in working memory, attention and vigilance, verbal learning andmemory, visual learning and memory, reasoning and problem solving, andin particular, for example, in executive function, task processing speedand/or social cognition. Cognitive disorders are known to exhibitattention deficit, disorganized thought, slow retarded thinking,comprehension difficulty, low attention, loss of problem solvingability, imprecise memory, difficulties in expressing thoughts and/or inintegration of thought, sense and behavior, or in erasing unreasonablethoughts. The terms “cognitive disorder” and “cognitive deficit” areinterchangeable.

The term “treatment” may be taken to include suppression and alleviation(regression) of diseases, disorders, or conditions associated withcognitive impairment in animals that have never been diagnosed with suchdiseases, disorders, or conditions caused by cognitive impairment, butthat are apt to such diseases, disorders, or conditions. Accordingly,the term “therapeutically effective amount” refers to an effective doseof a clinical marker necessary to alleviate or reduce symptoms ofdiseases to be treated, or an effective dose of an effective activecompound for reducing or retarding onset of such symptoms, which may beempirically determined through experiment in an in vivo and/or in vitromodel of a disease to be treated.

In some embodiments, the pharmaceutical composition may be formulated inany form to be administered by any suitable route, for example, by oral,rectal, nasal, pulmonary, topical, transdermal, intracisternal,intraperitoneal, vaginal and parenteral (including subcutaneous,intramuscular, intrathecal, intravenous, and intradermal) route, theoral route being preferred. For oral administration, the pharmaceuticalcomposition may include a pharmaceutically acceptable vehicle commonlyused in the art. In some embodiments, for oral liquid formulations suchas suspensions, syrups, elixirs, and solutions, examples of vehicles arewater, glycol, oil, and alcohol. For solid formulations such as pills,capsules, lozenges, examples of vehicles are starch, sugar, kaoline,lubricants, binders, and disintegrants. It will be appreciated that thepreferred route will depend on the general condition, age of the subjectto be treated, the nature of the condition to be treated, and the activeingredient chosen. In some embodiments, the pharmaceutical compositionmay be prepared in unit dosage form in terms of convenientadministration and dose consistency.

In some embodiments, the pharmaceutical composition may be administeredby any suitable route, for example, by parenteral route in the form ofinjections, or by oral route in the form of, for example, tablets,capsules, powders, granules, pellets, troches, dragees, pills, lozenges,aqueous or non-aqueous solutions, suspensions, water-in-oil oroil-in-water emulsions, elixirs, or syrups. For parenteraladministration, the pharmaceutical composition may be prepared asdispersions, suspension, emulsions, sterile injection solutions, ordispersions containing sterile powder. The pharmaceutical composition isalso available as a depot injection. Other suitable administration formsof the pharmaceutical composition are suppositories, sprays, ointments,creams, gels, inhalations, and skin patches. The pharmaceuticalcomposition may be prepared in any of the above-listed forms using anymethod known in the art. Any pharmaceutically acceptable vehiclediluent, excipient, or other additives that are commonly used in the artmay be used.

In some embodiments, for clinical purposes, the pharmaceuticalcomposition may be administered in a unit dose form of about 0.001-100mg/kg or in a multi-dose form. A total daily dose of the activecompounds disclosed in the present specification may be from about 0.001mg/kg to about 100 mg/kg per body weight, and in some embodiments, maybe from about 0.01 mg/kg to about 10 mg/kg per body weight, but is notlimited thereto, which depends on the generic conditions of a patientand the activity of the active compounds administered. In someembodiments, the pharmaceutical composition may be administered aboutone to three times a day. In some circumstances, the pyridone derivativecompound of Formula I may be used in formulating prodrug-type effectivepharmaceutical compositions.

In some embodiments, the pharmaceutical composition may further includeother auxiliary components that do not inhibit or help the function ofthe active components, and may be formulated in any of a variety offorms known in the art.

According to another aspect of the present disclosure, there is provideda treatment method of a cognitive impairment, the method includingcontacting a subject to be treated with the pharmaceutical compositiondescribed above. The contacting may be performed in vitro or in vivo.The in vivo contacting may include administering the pharmaceuticalcomposition to the subject. The subject may be cells, tissues, organics,or individuals. In some embodiments, the pharmaceutical composition maybe administered to a cell, tissue, or organ by direct contact of thepharmaceutical composition after dissolution in a suitable buffersolution, or may be parenterally administrated to an individual. Sincedescried above, the pharmaceutical composition and administration methodused in the treatment will not be described herein in detail. Thesubject to which the pharmaceutical composition is administered may beany animal, for example, humans, or non-humans such as dogs, cats, andmice.

Advantageous Effects

In some embodiments, the pharmaceutical composition may effectivelyprevent or treat cognitive disorders associated with cognitiveimpairments.

Mode of the Invention

One or more embodiments of the present disclosure will now be describedin detail with reference to the following examples. However, theseexamples are for illustrative purposes only and are not intended tolimit the scope of the one or more embodiments of the presentdisclosure.

Example 1 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-thiazolyl)-3-pyridinecarboxamide

Example 1-1 Synthesis of dimethyl 4-(methoxymethylene)-2-pentanedioate

52 mL (0.73 mmol) of acetylchloride was slowly dropwise added into amixed solution of 500 mL of methanol and 50 g (0.36 mol) of coumalicacid at about 0° C. for about 10 minutes while stirring. The resultingreaction solution was stirred under reflux for about 10 hours. Aftertermination of the reaction was determined by liquid chromatography, thereaction product was distilled using methanol under reduced pressure toobtain a compound. The compound was extracted three times with water andethyl acetate, and an organic phase was purified at a reduced pressureusing column chromatography (hexane:ethylacetate=1:5), thereby obtaininga target compound (Actual yield: 38 g, Percent yield: 53%).

(Major/minor ratio=5.8:1)

¹H-NMR (CDCl₃, 200 MHz, major) δ7.64 (s, 1H), 7.58 (d, 1H), 6.62 (d,1H), 4.02 (s, 3H), 3.73 (m, 6H)

¹H-NMR (CDCl₃, 200 MHz, minor) δ8.87 (s, 1H), 8.31 (d, 1H), 6.34 (d,1H), 3.89 (s, 3H), 3.73 (m, 6H)

Example 1-2 Synthesis of methyl6-oxo-1-(2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylate

After 2 g (9.9 mmol) of dimethyl 4-(methoxymethylene)2-pentenedioateobtained in Example 1-1 was dissolved in 10 mL of DMF, 1 g (9.9 mmol) of2-aminothiazole was added to the solution. Afterward, the resultingreaction solution was stirred under reflux at about 150° C. for 6 hours.After termination of the reaction was determined by liquidchromatography, the solvent was removed in vacuo and was then washedusing brine, followed by drying using magnesium sulfate, and filtration.After distillation under reduced pressure, the resulting product waspurified using column chromatography (hexane:ethylacetate=1:3) to obtaina target compound (Actual yield: 1 g, Percent yield: 43%).

¹H-NMR (CDCl₃, 500 MHz) δ9.65 (s, 1H), 7.99 (d, 1H), 7.75 (s, 1H), 7.34(s, 1H), 6.79 (d, 1H), 3.95 (s, 3H)

Example 1-3 Synthesis of methyl6-oxo-1-(2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid

After 680 mg (2.88 mmol) of methyl6-oxo-1-(2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylate was dissolved in12 mL of methanol and 4 mL of water, 207 mg (8.64 mmol) of lithiumhydroxide was added to the solution. Afterward, the resulting reactionsolution was stirred at about 75° C. for 5 hours. After termination ofthe reaction was determined by liquid chromatography, the solvent wasremoved in vacuo, and aqueous HCl was then added to the reactionsolution to titrate until pH 2 was reached. The resulting solid compoundwas filtrated to obtain a target compound (Actual yield: 466 mg, Percentyield: 73%).

¹H-NMR (DMSO-d₆, 500 MHz) δ13.29 (s, br, 1H), 9.40 (s, 1H), 7.92 (d,1H), 7.81 (s, 1H), 7.69 (s, 1H), 6.76 (d, 2H)

Example 1-4 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-thiazolyl)-3-pyridinecarboxamide

N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-thiazolyl)-3-pyridinecarboxamidewas synthesized using one of the following methods.

Method 1:

After 720 mg (3.15 mmol) of6-oxo-1-(2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid wasdissolved in 20 mL of tetrahydrofuran and 2 mL of DMF, 450 mg (3.78mmol) of quinuclidine dihydrochloride and 1.28 g (9.43 mmol) ofdiethylisopropylamide were added to the solution. After the reactionsolution was stirred at room temperature for about 30 minutes, 1.4 g(3.78 mmol) of O-(benzotriazole-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) was added to the reaction solution, thisreaction solution was stirred at room temperature for about 24 hours.After termination of the reaction was determined by liquidchromatography, the solvent was removed in vacuo, followed by extractionthree times with chloroform and an aqueous NaOH solution (pH 12) andpurification using liquid chromatography (chloroform:methanol:ammoniawater=10:1:0.1) to obtain a target compound (Actual yield: 676 mg,Percent yield: 67%).

Method 2:

After dissolution of 200 mg (0.90 mmol) of6-oxo-1-(2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid in 10 mL ofdichloromethane, 363 mg (2.86 mmol) of oxalyl chloride was added to thesolution, and a catalytic amount of DMF was then added thereto. Afterbeing stirred at room temperature for about 2 hours, the solvent wasremoved in vacuo. After addition of 220 mg (1.36 mmol) of quinuclidinedihydrochloride to 10 mL of acetonitrile, 445 mg (3.45 mmol) ofdiethylisopropylamide was added to the solution. This reaction solutionwas stirred at room temperature for about 1 hours. After addition of thereaction mixture distilled under reduced pressure to acetonitrile, thequinuclidine dihydrochloride reaction solution was slowly added thereto,followed by stirring at room temperature for about 24 hours and thesolvent was removed in vacuo. The resulting compound was extracted threetimes with chloroform and an aqueous NaOH solution (pH=12), and was thenpurified using liquid chromatography (chloroform:methanol:ammoniawater=10:1:0.1) to obtain a target compound (Actual yield: 95 mg,Percent yield: 32%).

¹H-NMR (CDCl₃, 500 MHz) δ9.26 (s, 1H), 7.86 (d, 1H), 7.55 (d, 1H), 7.24(d, 1H), 7.19 (br, 1H), 6.65 (d, 1H), 4.13 (m, 1H), 3.39 (m, 1H), 3.01(m, 1H), 2.80 (m, 4H), 2.05 (m, 1H), 1.86 (m, 1H), 1.71 (m, 2H), 1.50(m, 1H)

Example 2 Synthesis ofN-[(3R)-1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-thiazolyl)-3-pyridinecarboxamide

6-Oxo-1-(2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid wassynthesized in the same manner as in Example 1-2 and Example 1-3. Atarget compound was obtained from the synthesized6-oxo-1-(2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid and3R-quinuclidine dihydrochloride in the same manner as in Example 1-4 andMethod 1.

¹H-NMR (CDCl₃, 500 MHz) δ9.26 (s, 1H), 7.86 (d, 1H), 7.55 (d, 1H), 7.24(d, 1H), 7.19 (br, 1H), 6.65 (d, 1H), 4.13 (m, 1H), 3.39 (m, 1H), 3.01(m, 1H), 2.80 (m, 4H), 2.05 (m, 1H), 1.86 (m, 1H), 1.71 (m, 2H), 1.50(m, 1H)

Example 3 Synthesis ofN-[(3S)-1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-thiazolyl)-3-pyridinecarboxamide

6-Oxo-1-(2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid wassynthesized in the same manner as in Example 1-2 and Example 1-3. Atarget compound was obtained from the synthesized6-oxo-1-(2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid and3S-quinuclidine dihydrochloride in the same manner as in Example 1-4 andMethod 1.

¹H-NMR (CDCl₃, 500 MHz) δ9.26 (s, 1H), 7.86 (d, 1H), 7.55 (d, 1H), 7.24(d, 1H), 7.19 (br, 1H), 6.65 (d, 1H), 4.13 (m, 1H), 3.39 (m, 1H), 3.01(m, 1H), 2.80 (m, 4H), 2.05 (m, 1H), 1.86 (m, 1H), 1.71 (m, 2H), 1.50(m, 1H)

Example 4 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-pyridinyl)-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 2-aminopyridine was used as a starting material.

¹H-NMR (CDCl₃, 500 MHz) δ8.61 (s, 1H), 8.51 (s, 1H), 7.89 (m, 2H), 7.78(d, 1H), 7.40 (m, 1H), 6.67 (d, 1H), 6.18 (br, d, 1H), 4.12 (m, 1H),3.44 (m, 1H), 2.86 (m, 4H), 2.60 (m, 1H), 2.04 (m, 1H), 1.72 (m, 3H),1.54 (m, 1H)

Example 5 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(3-pyridinyl)-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 3-aminopyridine was used as a starting material.

¹H-NMR (CDCl₃, 500 MHz) δ8.75 (s, 1H), 8.69 (m, 1H), 8.11 (m, 1H), 7.85(m, 1H), 7.52 (m, 1H), 7.49 (m, 1H), 6.72 (m, 1H), 6.03 (br, 1H), 4.14(m, 1H), 3.49 (m, 1H), 2.89 (m, 4H), 2.61 (m, 1H), 2.05 (m, 1H), 1.75(m, 3H), 1.58 (m, 1H)

Example 6 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-chloro-2-pyridinyl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 2-amino-5-chloropyridine was used as a startingmaterial.

¹H-NMR (CDCl₃, 500 MHz) δ8.47 (s, 1H), 8.08 (m, 1H), 7.81 (d, 1H), 7.74(d, 1H), 7.52 (d, 1H), 6.70 (d, 1H), 6.05 (br, 1H), 4.13 (m, 1H), 3.48(m, 1H), 2.84 (m, 4H), 2.57 (m, 1H), 2.03 (m, 1H), 1.73 (m, 3H), 1.57(m, 1H)

Example 7 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-phenyl-2-pyridine-1-yl)-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 2-amino-5-phenylpyridine was used as a startingmaterial.

¹H-NMR (CDCl₃, 500 MHz) δ8.80 (s, 1H), 8.59 (m, 1H), 8.01 (m, 2H), 7.84(m, 1H), 7.57 (m, 2H), 7.47 (m, 3H), 6.68 (d, 1H), 6.43 (br, 1H), 4.19(m, 1H), 3.42 (m, 1H), 3.08 (m, 1H), 2.84 (m, 4H), 2.10 (m, 1H), 1.77(m, 3H), 1.58 (m, 1H)

Example 8 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(3-isoxazolyl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 3-aminoisoxazole was used as a starting material.

¹H-NMR (CDCl₃, 500 MHz) δ8.58 (s, 1H), 8.48 (s, 1H), 7.90 (m, 1H), 7.17(s, 1H), 6.95 (br, 1H), 6.63 (d, 1H), 4.25 (m, 1H), 3.48 (m, 1H), 3.25(m, 1H), 2.91 (m, 4H), 2.14 (m, 1H), 1.78 (m, 3H), 1.58 (m, 1H)

Example 9 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-[3-phenyl-5-isoxazolyl)-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 5-amino-3-phenylisoxazole was used as a startingmaterial.

¹H-NMR (DMSO-d₆, 500 MHz) δ8.66 (s, 1H), 8.33 (m, 1H), 8.02 (d, 1H),7.95 (m, 2H), 7.57 (m, 3H), 7.50 (s, 1H), 6.70 (d, 1H), 3.96 (m, 1H),3.19 (m, 1H), 2.89 (m, 1H), 2.70 (m, 4H), 1.81 (m, 2H), 1.61 (m, 2H),1.34 (m, 1H)

Example 10 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-methyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 2-amino-5-methylthiazole was used as a startingmaterial.

¹H-NMR (CDCl₃, 500 MHz) δ9.23 (s, 1H), 7.85 (d, 1H), 7.33 (s, 1H), 6.73(d, 1H), 6.56 (br, 1H), 4.14 (m, 1H), 3.42 (m, 1H), 2.82 (m, 4H), 2.65(m, 1H), 2.48 (s, 3H), 2.04 (m, 1H), 1.74 (m, 3H), 1.56 (m, 1H)

Example 11 Synthesis ofN-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-methyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide

6-Oxo-1-(5-methyl-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid wassynthesized in the same manner as in Example 1-2 and Example 1-3, exceptthat 2-amino-5-methylthiazole was used as a starting material. A targetcompound was obtained from the synthesized6-oxo-1-(5-methyl-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid and3R-quinuclidine dihydrochloride in the same manner as in Example 1-4 andMethod 1.

¹H-NMR (CDCl₃, 500 MHz) δ9.23 (s, 1H), 7.85 (d, 1H), 7.33 (s, 1H), 6.73(d, 1H), 6.56 (br, 1H), 4.14 (m, 1H), 3.42 (m, 1H), 2.82 (m, 4H), 2.65(m, 1H), 2.48 (s, 3H), 2.04 (m, 1H), 1.74 (m, 3H), 1.56 (m, 1H)

Example 12 Synthesis ofN-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-methyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide

6-Oxo-1-(5-methyl-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid wassynthesized in the same manner as in Example 1-2 and Example 1-3, exceptthat 2-amino-5-methylthiazole was used as a starting material. A targetcompound was obtained from the synthesized6-oxo-1-(5-methyl-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid and3S-quinuclidine dihydrochloride in the same manner as in Example 1-4 andMethod 1.

¹H-NMR (CDCl₃, 500 MHz) δ9.23 (s, 1H), 7.85 (d, 1H), 7.33 (s, 1H), 6.73(d, 1H), 6.56 (br, 1H), 4.14 (m, 1H), 3.42 (m, 1H), 2.82 (m, 4H), 2.65(m, 1H), 2.48 (s, 3H), 2.04 (m, 1H), 1.74 (m, 3H), 1.56 (m, 1H)

Example 13 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-ethyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 and

Method 1, except that 2-amino-5-ethylthiazole was used as a startingmaterial.

¹H-NMR (CDCl₃, 500 MHz) δ9.30 (s, 1H), 7.96 (d, 1H), 7.30 (s, 1H), 7.18(br, d, 1H), 6.72 (d, 1H), 4.24 (m, 1H), 3.45 (m, 1H), 3.21 (m, 1H),3.02 (m, 1H), 2.88 (m, 5H), 2.16 (m, 1H), 1.93 (m, 1H), 1.80 (m, 2H),1.58 (m, 1H), 1.34 (t, 3H)

Example 14 Synthesis ofN-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-ethyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide

6-Oxo-1-(5-ethyl-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid wassynthesized in the same manner as in Example 1-2 and Example 1-3, exceptthat 2-amino-5-ethylthiazole was used as a starting material. A targetcompound was obtained from the synthesized6-oxo-1-(5-ethyl-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid and3R-quinuclidine dihydrochloride in the same manner as in Example 1-4 andMethod 1.

¹H-NMR (CDCl₃, 500 MHz) δ9.30 (s, 1H), 7.96 (d, 1H), 7.30 (s, 1H), 7.18(br, d, 1H), 6.72 (d, 1H), 4.24 (m, 1H), 3.45 (m, 1H), 3.21 (m, 1H),3.02 (m, 1H), 2.88 (m, 5H), 2.16 (m, 1H), 1.93 (m, 1H), 1.80 (m, 2H),1.58 (m, 1H), 1.34 (t, 3H)

Example 15 Synthesis ofN-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-ethyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide

6-Oxo-1-(5-ethyl-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid wassynthesized in the same manner as in Example 1-2 and Example 1-3, exceptthat 2-amino-5-ethylthiazole was used as a starting material. A targetcompound was obtained from the synthesized6-oxo-1-(5-ethyl-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid and3S-quinuclidine dihydrochloride in the same manner as in Example 1-4 andMethod 1.

¹H-NMR (CDCl₃, 500 MHz) δ9.30 (s, 1H), 7.96 (d, 1H), 7.30 (s, 1H), 7.18(br, d, 1H), 6.72 (d, 1H), 4.24 (m, 1H), 3.45 (m, 1H), 3.21 (m, 1H),3.02 (m, 1H), 2.88 (m, 5H), 2.16 (m, 1H), 1.93 (m, 1H), 1.80 (m, 2H),1.58 (m, 1H), 1.34 (t, 3H)

Example 16 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-propyl-2-thiazolyl)-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 2-amino-5-propylthiazole was used as a startingmaterial.

¹H-NMR (CDCl₃, 500 MHz) δ9.27 (s, 1H), 7.90 (d, 1H), 7.31 (s, 1H), 6.84(br, 1H), 6.72 (d, 1H), 4.18 (m, 1H), 3.43 (m, 1H), 3.09 (m, 1H), 2.88(m, 4H), 2.80 (t, 2H), 2.11 (m, 1H), 1.86 (m, 1H), 1.73 (m, 4H), 1.56(m, 1H), 1.00 (t, 3H)

Example 17 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-propan-2-yl-2-thiazolyl)-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 2-amino-5-isopropylthiazole was used as a startingmaterial.

¹H-NMR (CDCl₃, 500 MHz) δ9.28 (s, 1H), 7.96 (d, 1H), 7.29 (br, d, 1H),6.71 (d, 1H), 4.23 (m, 1H), 3.42 (m, 1H), 3.22 (m, 2H), 2.93 (m, 4H),2.16 (m, 1H), 1.94 (m, 1H), 1.80 (m, 2H), 1.53 (m, 1H), 1.35 (d, 6H)

Example 18 Synthesis ofN-[(3R)-1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-propan-2-yl-2-thiazolyl)-3-pyridinecarboxamide

6-Oxo-1-(5-propan-2-yl-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylicacid was synthesized in the same manner as in Example 1-2 and Example1-3, except that 2-amino-5-isopropylthiazole was used as a startingmaterial. A target compound was obtained from the synthesized6-oxo-1-(5-propanl-2-yl-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylicacid and 3R-quinuclidine dihydrochloride in the same manner as inExample 1-4 and Method 1.

¹H-NMR (CDCl₃, 500 MHz) δ9.28 (s, 1H), 7.96 (d, 1H), 7.29 (br, d, 1H),6.71 (d, 1H), 4.23 (m, 1H), 3.42 (m, 1H), 3.22 (m, 2H), 2.93 (m, 4H),2.16 (m, 1H), 1.94 (m, 1H), 1.80 (m, 2H), 1.53 (m, 1H), 1.35 (d, 6H)

Example 19 Synthesis ofN-[(3S)-1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-propan-2-yl-2-thiazolyl)-3-pyridinecarboxamide

6-Oxo-1-(5-propan-2-yl-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylicacid was synthesized in the same manner as in Example 1-2 and Example1-3, except that 2-amino-5-isopropylthiazole was used as a startingmaterial. A target compound was obtained from the synthesized6-oxo-1-(5-propanl-2-yl-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylicacid and 3S-quinuclidine dihydrochloride in the same manner as inExample 1-4 and Method 1.

¹H-NMR (CDCl₃, 500 MHz) δ9.28 (s, 1H), 7.96 (d, 1H), 7.29 (br, d, 1H),6.71 (d, 1H), 4.23 (m, 1H), 3.42 (m, 1H), 3.22 (m, 2H), 2.93 (m, 4H),2.16 (m, 1H), 1.94 (m, 1H), 1.80 (m, 2H), 1.53 (m, 1H), 1.35 (d, 6H)

Example 20 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-tert-butyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 2-amino-5-tert-butylthiazole was used as astarting material.

¹H-NMR (CDCl₃, 500 MHz) δ9.25 (s, 1H), 7.86 (d, 1H), 7.27 (s, 1H), 6.87(br, 1H), 6.70 (d, 1H), 4.19 (m, 1H), 3.45 (m, 1H), 3.08 (m, 1H), 2.89(m, 4H), 2.11 (m, 1H), 1.90 (m, 1H), 1.76 (m, 2H), 1.57 (m, 1H), 1.42(s, 9H)

Example 21 Synthesis ofN-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-[5-tert-butyl-2-thiazolyl]-6-oxo-3-pyridinecarboxamide

6-Oxo-1-(5-tert-butyl-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acidwas synthesized in the same manner as in Example 1-2 and Example 1-3,except that 2-amino-5-tert-butylthiazole was used as a startingmaterial. A target compound was obtained from the synthesized6-oxo-1-(5-tert-butyl-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acidand 3R-quinuclidine dihydrochloride in the same manner as in Example 1-4and Method 1.

¹H-NMR (CDCl₃, 500 MHz) δ9.25 (s, 1H), 7.86 (d, 1H), 7.27 (s, 1H), 6.87(br, 1H), 6.70 (d, 1H), 4.19 (m, 1H), 3.45 (m, 1H), 3.08 (m, 1H), 2.89(m, 4H), 2.11 (m, 1H), 1.90 (m, 1H), 1.76 (m, 2H), 1.57 (m, 1H), 1.42(s, 9H)

Example 22 Synthesis ofN-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-[5-tert-butyl-2-thiazolyl]-6-oxo-3-pyridinecarboxamide

6-Oxo-1-(5-tert-butyl-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acidwas synthesized in the same manner as in Example 1-2 and Example 1-3,except that 2-amino-5-tert-butylthiazole was used as a startingmaterial. A target compound was obtained from the synthesized6-oxo-1-(5-tert-butyl-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acidand 3S-quinuclidine dihydrochloride in the same manner as in Example 1-4and Method 1.

¹H-NMR (CDCl₃, 500 MHz) δ9.25 (s, 1H), 7.86 (d, 1H), 7.27 (s, 1H), 6.87(br, 1H), 6.70 (d, 1H), 4.19 (m, 1H), 3.45 (m, 1H), 3.08 (m, 1H), 2.89(m, 4H), 2.11 (m, 1H), 1.90 (m, 1H), 1.76 (m, 2H), 1.57 (m, 1H), 1.42(s, 9H)

Example 23 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-cyclopentyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 2-amino-5-cyclopentylthiazole was used as astarting material.

¹H-NMR (CDCl₃, 500 MHz) δ9.17 (s, 1H), 7.80 (d, 1H), 7.21 (s, 1H), 6.95(br, 1H), 6.64 (d, 1H), 4.10 (m, 1H), 3.37 (m, 1H), 3.19 (m, 1H), 2.99(m, 1H), 2.81 (m, 4H), 2.12 (m, 2H), 2.04 (m, 1H), 1.78 (m, 3H), 1.66(m, 6H), 1.50 (m, 1H)

Example 24 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-cyclohexyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 2-amino-5-cyclohexylthiazole was used as astarting material.

¹H-NMR (CDCl₃, 500 MHz) δ9.33 (s, 1H), 8.01 (d, 1H), 7.52 (br, 1H), 7.26(s, 1H), 6.68 (d, 1H), 4.32 (m, 1H), 3.47 (m, 1H), 3.39 (m, 1H), 3.32(m, 1H), 3.05 (m, 3H), 2.83 (m, 1H), 2.24 (m, 1H), 2.04 (m, 3H), 1.87(m, 4H), 1.74 (m, 1H), 1.65 (m, 1H), 1.49 (m, 4H), 1.23 (m, 1H)

Example 25 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-phenyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 2-amino-5-phenylthiazole was used as a startingmaterial.

¹H-NMR (CDCl₃, 500 MHz) δ9.53 (s, 1H), 7.93 (d, 2H), 7.85 (d, 1H), 7.45(m, 4H), 6.79 (d, 1H), 6.63 (br, 1H), 4.21 (m, 1H), 3.46 (m, 1H), 3.06(m, 1H), 2.92 (m, 4H), 2.06 (m, 1H), 1.84 (m, 3H), 1.68 (m, 1H)

Example 26 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-chloro-2-thiazolyl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 2-amino-5-chlorothiazole was used as a startingmaterial.

¹H-NMR (CDCl₃, 500 MHz) δ9.13 (s, 1H), 7.85 (d, 1H), 7.44 (s, 1H), 6.92(br, 1H), 6.69 (d, 1H), 4.13 (m, 1H), 3.41 (m, 1H), 3.00 (m, 1H), 2.28(m, 4H), 2.06 (m, 1H), 1.84 (m, 1H), 1.71 (m, 2H), 1.52 (m, 1H)

Example 27 Synthesis ofN-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-chloro-2-thiazolyl)-6-oxo-3-pyridinecarboxamide

6-Oxo-1-(5-chloro-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid wassynthesized in the same manner as in Example 1-2 and Example 1-3, exceptthat 2-amino-5-chlorothiazole was used as a starting material. A targetcompound was obtained from the synthesized6-oxo-1-(5-chloro-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid and3R-quinuclidine dehydrochloride in the same manner as in Example 1-4 andMethod 1.

¹H-NMR (CDCl₃, 500 MHz) δ9.13 (s, 1H), 7.85 (d, 1H), 7.44 (s, 1H), 6.92(br, 1H), 6.69 (d, 1H), 4.13 (m, 1H), 3.41 (m, 1H), 3.00 (m, 1H), 2.28(m, 4H), 2.06 (m, 1H), 1.84 (m, 1H), 1.71 (m, 2H), 1.52 (m, 1H)

Example 28 Synthesis ofN-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-chloro-2-thiazolyl)-6-oxo-3-pyridinecarboxamide

6-Oxo-1-(5-chloro-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid wassynthesized in the same manner as in Example 1-2 and Example 1-3, exceptthat 2-amino-5-chlorothiazole was used as a starting material. A targetcompound was obtained from the synthesized6-oxo-1-(5-chloro-2-thiazolyl)-1,6-dihydro-3-pyridinecarboxylic acid and3S-quinuclidine dehydrochloride in the same manner as in Example 1-4 andMethod 1.

¹H-NMR (CDCl₃, 500 MHz) δ9.13 (s, 1H), 7.85 (d, 1H), 7.44 (s, 1H), 6.92(br, 1H), 6.69 (d, 1H), 4.13 (m, 1H), 3.41 (m, 1H), 3.00 (m, 1H), 2.28(m, 4H), 2.06 (m, 1H), 1.84 (m, 1H), 1.71 (m, 2H), 1.52 (m, 1H)

Example 29 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-[5-(phenylmethyl)-2-thiazolyl)]-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 5-benzyl-1,3-thiazolyl-2-aniline was used as astarting material.

¹H-NMR (CDCl₃, 500 MHz) δ9.23 (s, 1H), 7.82 (d, 1H), 7.32 (m, 6H), 6.72(d, 1H), 6.36 (br, 1H), 4.16 (s, 2H), 4.12 (m, 1H), 3.44 (m, 1H), 2.89(m, 4H), 2.62 (m, 1H), 2.04 (m, 1H), 1.72 (m, 3H), 1.52 (m, 1H)

Example 30 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-methyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 2-amino-4-methylthiazole was used as a startingmaterial.

¹H-NMR (CDCl₃, 500 MHz) δ9.34 (s, 1H), 7.83 (d, 1H), 6.87 (s, 1H), 6.78(d, 1H), 6.40 (br, 1H), 4.18 (m, 1H), 3.42 (m, 1H), 2.84 (m, 4H), 2.65(m, 1H), 2.51 (s, 3H), 2.08 (m, 1H), 1.78 (m, 3H), 1.58 (m, 1H)

Example 31 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-(4-chlorophenyl)-2-thiazolyl]-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 and

Method 1, except that 2-amino-4-chlorophenylthiazole was used as astarting material.

¹H-NMR (CDCl₃, 500 MHz) δ9.52 (s, 1H), 7.87 (m, 2H), 7.81 (m, 1H), 7.45(s, 1H), 7.41 (m, 2H), 6.80 (m, 1H), 6.38 (br, 1H), 4.13 (m, 1H), 3.47(m, 1H), 3.03 (m, 1H), 2.83 (m, 3H), 2.77 (m, 1H), 2.11 (m, 1H), 1.86(m, 3H), 1.69 (m, 1H)

Example 32 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4,5-dimethyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 2, except that 2-amino-4,5-dimethylthiazole was used as astarting material.

¹H-NMR (CDCl₃, 500 MHz) δ9.18 (s, 1H), 7.80 (d, 1H), 7.19 (br, d, 1H),6.60 (d, 1H), 4.12 (m, 1H), 3.35 (m, 1H), 3.02 (m, 1H), 2.84 (m, 4H),2.29 (s, 3H), 2.08 (s, 3H), 2.06 (m, 1H), 1.87 (m, 1H), 1.72 (m, 2H),1.50 (m, 1H)

Example 33 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(1,3-benzothiazole-2-yl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 2-amino-1,3-benzothiazole was used as a startingmaterial.

¹H-NMR (CDCl₃, 500 MHz) δ9.45 (s, 1H), 7.98 (m, 3H), 7.56 (m, 1H), 7.52(m, 1H), 6.84 (m, 1H), 6.32 (br, 1H), 4.17 (m, 1H), 3.44 (m, 1H), 3.04(m, 1H), 2.94 (m, 3H), 2.65 (m, 1H), 2.01 (m, 1H), 1.84 (m, 3H), 1.60(m, 1H)

Example 34 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-methoxy-1,3-benzothiazole-2-yl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 2-amino-4-methoxy-1,3-benzothiazole was used as astarting material.

¹H-NMR (CDCl₃, 500 MHz) δ9.50 (s, 1H), 7.97 (d, 1H), 7.54 (d, 1H), 7.38(m, 1H), 6.84 (d, 1H), 6.69 (d, 1H), 6.53 (br, 1H), 4.14 (m, 1H), 4.08(m, 3H), 3.43 (m, 1H), 2.71 (m, 4H), 2.68 (m, 1H), 2.08 (m, 1H), 1.73(m, 3H), 1.58 (m, 1H)

Example 35 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-[5,6-dimethyl-1,3-benzothiazole-2-yl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 2-amino-5,6-dimethoxy-1,3-benzothiazole was usedas a starting material.

¹H-NMR (CDCl₃, 500 MHz) δ9.46 (s, 1H), 8.65 (d, 1H), 8.09 (d, 1H), 7.84(d, 2H), 6.80 (d, 1H), 4.14 (m, 1H), 3.46 (m, 1H), 2.89 (m, 4H), 2.49(m, 6H), 2.38 (m, 1H), 2.07 (m, 1H), 1.79 (m, 3H), 1.62 (m, 1H)

Example 36 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2,1,3-benzothiazole-4-yl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 4, except that 4-amino-2,1,3-benzothiazole was used as a startingmaterial.

¹H-NMR (CDCl₃, 500 MHz) δ8.18 (s, 1H), 8.16 (d, 1H), 7.80 (m, 1H), 7.78(m, 1H), 7.68 (m, 1H), 6.66 (d, 1H), 6.42 (br, d, 1H), 4.05 (m, 1H),3.33 (m, 1H), 2.84 (m, 4H), 2.54 (m, 1H), 1.95 (m, 1H), 1.67 (m, 3H),1.46 (m, 1H)

Example 37 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(1,3-benzothiazole-6-yl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 6-amino-1,3-benzothiazole was used as a startingmaterial.

¹H-NMR (CDCl₃, 500 MHz) δ8.93 (s, 1H), 8.23 (m, 1H), 8.20 (s, 1H), 8.02(s, 1H), 7.79 (d, 1H), 7.57 (d, 1H), 6.65 (d, 1H), 6.56 (br, d, 1H),4.15 (m, 1H), 3.39 (m, 1H), 2.88 (m, 4H), 2.72 (m, 1H), 2.01 (m, 1H),1.76 (m, 3H), 1.53 (m, 1H)

Example 38 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-methyl-2-phenyl-3-pyrazolyl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 3-amino-5-methyl-2-phenylpyrazole was used as astarting material.

¹H-NMR (CDCl₃, 500 MHz) δ8.97 (s, 1H), 8.51 (s, 1H), 8.23 (d, 2H), 7.52(m, 3H), 7.33 (m, 2H), 6.44 (br, 1H), 4.23 (m, 1H), 3.48 (m, 1H), 2.91(m, 3H), 2.86 (m, 2H), 2.67 (m, 3H), 1.98 (m, 1H), 1.75 (m, 3H), 1.59(m, 1H)

Example 39 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(1-isoquinolinyl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 1-aminoisoquinoline was used as a startingmaterial.

¹H-NMR (CDCl₃, 500 MHz) δ9.10 (d, 1H), 8.92 (d, 1H), 8.50 (s, 1H), 7.80(m, 3H), 7.61 (d, 1H), 7.43 (m, 2H), 5.98 (br, 1H), 4.13 (m, 1H), 3.63(m, 1H), 2.87 (m, 4H), 2.58 (d, 1H), 2.07 (m, 1H), 1.93 (m, 2H), 1.52(1H), 1.43 (s, 1H)

Example 40 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-isoquinolinyl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 5 andMethod 1, except that 1-aminoisoquinoline was used as a startingmaterial.

¹H-NMR (CDCl₃, 500 MHz) δ9.38 (m, 1H), 8.59 (m, 1H), 8.18 (m, 1H), 8.05(m, 1H), 7.82 (m, 1H), 7.78 (m, 2H), 7.23 (m, 1H), 6.77 (d, 1H), 6.30(br, 1H), 4.11 (m, 1H), 3.41 (m, 1H), 2.85 (m, 4H), 2.61 (m, 1H), 2.05(m, 1H), 1.78 (m, 3H), 1.49 (m, 1H)

Example 41 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-quinolinyl)-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 5 andMethod 1, except that 1-aminoquinoline was used as a starting material.

¹H-NMR (CDCl₃, 500 MHz) δ8.90 (d, 1H), 8.23 (s, 1H), 8.12 (s, 1H), 7.80(t, 3H), 7.51 (m, 2H), 6.78 (d, 1H), 6.23 (br, 1H), 4.04 (m, 1H), 3.48(m, 1H), 2.81 (m, 4H), 2.59 (m, 1H), 1.93 (m, 1H), 1.87 (m, 2H), 1.64(m, 1H), 1.45 (m, 1H)

Example 42 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-1-[5-methyl-1,3,4-thiadiazole-2-yl)-6-oxo-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 2, except that 2-amino-5-methyl-1,3,4-thiadiazole was used as astarting material.

¹H-NMR (CDCl₃, 500 MHz) δ9.31 (s, 1H), 8.03 (d, 1H), 7.24 (br, s, 1H),6.78 (d, 1H), 4.21 (m, 1H), 3.39 (m, 1H), 3.12 (m, 1H), 2.91 (m, 4H),2.77 (s, 3H), 2.12 (m, 1H), 1.91 (m, 1H), 1.78 (m, 2H), 1.57 (m, 1H)

Example 43 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-phenyl-1,3,4-thiadiazole-2-yl)-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 2-amino-5-phenyl-1,3,4-thiadiazole was used as astarting material.

¹H-NMR (CDCl₃, 500 MHz) δ8.14 (s, 1H), 7.97 (m, 2H), 7.59 (m, 3H), 7.47(m, 1H), 7.41 (m, 1H), 5.99 (br, 1H), 4.11 (m, 1H), 3.42 (m, 1H), 2.82(m, 4H), 2.54 (m, 1H), 2.01 (m, 1H), 1.83 (m, 3H), 1.66 (m, 1H)

Example 44 Synthesis ofN-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-pyrazinyl)-3-pyridinecarboxamide

A target compound was obtained in the same manner as in Example 1 andMethod 1, except that 2-aminopyrazine was used as a starting material.

¹H-NMR (CDCl₃, 500 MHz) δ9.31 (s, 1H), 8.62 (m, 3H), 7.78 (m, 1H), 6.68(d, 1H), 6.31 (br, 1H), 4.09 (m, 1H), 3.41 (m, 1H), 2.87 (m, 4H), 2.65(m, 1H), 2.17 (m, 1H), 1.75 (m, 3H), 1.58 (m, 1H)

Example 45 Synthesis of(1-azabicyclo[2.2.2]octan-3-yl)-1-[5-methyl-1,3-thiadiazole-2-yl)-6-oxo-3-pyridinecarboxylate

Example 45-1 Synthesis of methyl1-(5-methyl-1,3-thiazole-2-yl)-1,6-dihydro-6-oxo-3-pyridinecarboxylate

A target compound was synthesized using 2-amino-5-methylthiazole in thesame manner as in Example 1-2.

Example 45-2 Synthesis of1-(5-methyl-1,3-thiazole-2-yl)-1,6-dihydro-6-oxo-3-pyridinecarboxylicacid

A target compound was obtained using methyl1-(5-methyl-1,3-thiazole-2-yl)-1,6-dihydro-6-oxo-3-pyridinecarboxylateand LiOH in the same manner as in Example 1-3.

Example 45-3 Synthesis of 6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carbonylchloride

After 510 mg (2.15 mmol) of1-(5-methyl-1,3-thiazole-2-yl)-1,6-dihydro-6-oxo-3-pyridinecarboxylicacid obtained in Example 45-2 was dissolved in 10 mL of toluene, 522 mg(4.30 mmol) of thionylchloride was added to the solution. Afterward, theresulting reaction solution was stirred under reflux at about 100° C.for 2 hours. After termination of the reaction was determined by liquidchromatography, the solvent was removed in vacuo. The resulting solidcompound was used in Example 45-4 without an additional purificationprocess.

Example 45-4 Synthesis of (1-Azabicyclo

[2.2.2]octan-3-yl)-1-[5-methyl-1,3-thiadiazole-2-yl)-6-oxo-3-pyridinecarboxylate

After dissolution of the mixed solution of6-oxo-1-phenyl-1,6-dihydropyridine-3-carbonyl chloride obtained inExample 45-3 in 5 mL of pyridine, 547 mg (4.30 mmol) of3-hydroxyquinuclidine was added thereto. Afterward, the resultingreaction solution was stirred at room temperature for about 3 days.After termination of the reaction was determined by liquidchromatography, the solvent was removed in vacuo. The resulting compoundwas extracted three times with water and chloroform, and the organicphase was purified using liquid chromatography(chloroform:methanol:ammonia water=10:1:0.1) to obtain a target compound(Actual yield: 357 mg, Percent yield: 48%).

¹H-NMR (CDCl₃, 500 MHz) δ9.52 (s, 1H), 7.92 (d, 1H), 7.35 (s, 1H), 6.72(d, 1H), 5.01 (m, 1H), 3.33 (m, 1H), 2.89 (m, 5H), 2.46 (s, 3H), 2.14(m, 1H), 1.94 (m, 1H), 1.72 (m, 1H), 1.60 (m, 1H), 1.48 (m, 1H)

Example 46 Synthesis of(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-propan-2-yl-1,3-thiazole-2-yl)-3-pyridinecarboxylate

A target compound was obtained in the same manner as in Example 45,except that 2-amino-5-isopropylthiazole was used as a starting material.

¹H-NMR (CDCl₃, 500 MHz) δ9.58 (s, 1H), 7.95 (d, 1H), 7.42 (s, 1H), 6.77(d, 1H), 5.07 (m, 1H), 3.38 (m, 1H), 3.26 (m, 1H), 2.87 (m, 5H), 2.21(m, 1H), 2.02 (m, 1H), 1.79 (m, 1H), 1.67 (m, 1H), 1.54 (m, 1H), 1.40(d, 6H)

Example 47 Measurement of Human α7 Nicotinic Acetylcholine Receptor(nAChR)'s Activity

Activity of heteromeric α7 nAChR was measured via FlexStation-Ca²⁺influx assay. In the present example, in consideration of α7 nAChR beingCa²⁺-permeable non-selective cationic channels, changes intracellularCa²⁺ concentration were measured using a fluorescent dye Calcium-3(available from Molecular Devices) and FlexStation II instrument(available from Molecular Devices).

Human CHRNA7 (NM_000746) cDNA ORF clone (C/N RC221382; Origene) andHuman RIC3 (NM_024557) cDNA ORF clone (C/N RC205179; Origene) weresubcloned into pcDNA2.1/Zeo(+) vector (available from Invitrogen, Co.)to construct HEK293T/17 cells (ATCC, CRL-11268) transfected with humanα7 nAChR. Afterward, the cells were suspended in growth media (consistedof Dulbecco's Modified Eagle's Media (DMEM, available from Invitrogen),a 10% heat-inactivated fetal bovine serum (FBS, available fromInvitrogen), 300 μg/ml Geneticin (available from Invitrogen), 250 μg/mlZeocin (available from Invitrogen), and 1× penicillin/streptomycin(available from Invitrogen)), followed by plating onto a Φ150 mm plate.Twenty-four hours prior to the start of the assay, grown cells in thesuspension were collected, followed by centrifugation and furthersuspension at a concentration of 5×10⁵ cells/mL in growth media. Thiscell suspension was dispensed to each well of a 96-well black plate(5×10⁴ cells/well) with a poly-D-lysine-coated transparent bottom(available from Biocoat, BD). The plate with the cells were incubated atabout 37° C. in 5% CO₂ for about 24 hours.

On the day of the assay, after removal of the growth media, the cellswere washed once with an assay buffer (7 mM Tris-Cl, 20 mM HEPES, 20 mMNaCl, 5 mM KCl, 0.8 mM MgSO₄, 4 mM CaCl₂, 120 mM NMDG, 5 mM D-glucose,pH 7.4), followed by addition of about 100 ul per well of a Calcium-3dye diluted with the assay buffer, and storage at room temperature forabout 1 hour. A test compound (10 mM stock in 100% dimethyl sulfoxide(DMSO)) was diluted with the assay buffer to various concentrations,from the highest at about 40 μM to be lower by ⅓, and PNU-120596(available from Sigma) for amplifying Ca²⁺ permeability signaling wasdiluted to about 30 μM with the assay buffer. Epibatidine (availablefrom Sigma) in a final concentration of about 1 μM was used as apositive control group.

To measure changes in intracellular Ca²⁺ concentration, after the platewas stored at room temperature for about 1 hour and the test compounddilution plate were put into FlexStation II equipment, fluorescence ofthe cells were measured for about 30 seconds prior to addition of drugs(the compounds), followed by addition of PNU-120596 and measurement ofchanges in fluorescence for about 120 seconds. After the cells wereexposed to the test compound, changes in fluorescence for about 90seconds were measured (excitation at 485 nm/emission at 525 nm). Thelargest fluorescence value at each concentration was recorded, and anEC₅₀ of the test compound was determined using non-linear regressionanalysis with relative fluorescence values relative to the positivecontrol group.

The results were represented as EC₅₀ values. For those compounds lackingdependency on concentration, relative fluorescence values were read at aconcentration with the highest fluorescence value among the compoundstested. This test was performed one time or more. Efficacies of thecompounds synthesized in some examples were tested using the same methodas above, and the results are shown in Tables 1 and 2 below. In Table1, + denotes an EC50 of 1000 nM or greater, ++ denotes an EC50 of from500 nM to 1000 nM, +++ denotes an EC50 of from 100 nM to about 500 nM,and ++++ denotes an EC50 of 100 nM or less.

TABLE 1 Example EC₅₀ of human α7 nAChR (nM) 1 +++ 2 +++ 3 +++ 6 + 7 +++9 + 10 +++ 11 ++++ 12 ++ 13 +++ 14 ++++ 15 +++ 16 +++ 17 +++ 18 ++++ 19+++ 20 +++ 21 +++ 22 ++ 23 +++ 24 +++ 25 ++ 26 ++++ 27 +++ 28 + 29 +++30 + 33 +++ 42 + 45 + 46 + +; 1000 nM or greater, ++; from 500 nm to1000 nM, +++; from 100 mM to 500 nM, ++++; 100 nM or less

Example 48 Novel Object Recognition Test (NORT) on Mice Administratedwith Pyridine Derivative Compound-Containing Composition

A NORT, which was first introduced by Ennaceur and Delacour, is acognitive memory test for measuring whether rats are able to rememberobjects with which they have had previous experience based on the natureof rats, i.e., preference to explore novel objects [Ennaceur A andDelacour J (1988) A new one-trial test for neurobiological studies ofmemory in rats. 1; Behavioral data. Behavioral Brain Res. 31; 47-59].This NOR test is a popular experimental method for measuring changes inmemory of objects in rodents administered with either anamnesia-inducing drug or other general drugs, by which memory recoveryefficacy of a test drug in the rodents administered with theamnesia-inducing drug is explored. In the present example, the test wasperformed in accord with the description of Bevins and Besheer [Bevins,R. A. & Besheer, J. Object recognition in rats and mice; a one-trialnon-matching-to-sample learning task to study ‘recognition memory’. NatProtoc. 2006; 1(3); 1306-11. (2006)]. Male ICR mice (available fromOrient Bio Inc., Korea) weighing from about 20 g to about 32 g wereorally administered a test compound dissolved in a 30% PEG at doses of0.03˜3 mg/kg and 10 ml/kg body weight. 30 minutes after theadministration, MK-801 (available from Sigma) dissolved in saline wassubcutaneously administered at doses of 0.1 mg/kg and 10 ml/kg bodyweight to induce amnesia. About 30 minutes after the administration ofMK-801, the mice were allowed to explore a rectangular stainless steelpillar or a circular plastic pillar which was previously placed in a boxfor about 5 minutes. About 24 hours after the exploration, one of thetwo objects previously presented was replaced with a new one (i.e., toinclude one rectangular stainless steel pillar and one circular plasticpillar), the times they took to explore were measured for about 5minutes. A recognition index (RI) was defined as:

[(Exploration time for novel object in test compound group/Explorationtime for all objects in test compound group)/(Exploration time for novelobject in MK801 group/Exploration time for all objects in MK801group)×100].

Table 2 below presents relative RIs of the compounds at a minimal doseresulting in half maximal activation (EC₅₀).

TABLE 2 Example NORT Relative RI (%)@MED 1 114.8% @0.03po 2 116.4%@0.01po 10 114.8% @0.3po 11 111.8% @0.03po 13 116.7% @0.3po 14 109.6%@0.03po 17 112.0% @0.3po 20 117.0% @0.3po 24 121.6% @0.03po 26 110.4%@0.3po 33 118.3% @0.01po

What is claimed is: 1-7. (canceled)
 8. A method for treating a cognitivedisorder in a patient, comprising: administering to the patient atherapeutically effective amount of a compound of Formula I:

or a pharmaceutically acceptable salt, solvate or hydrate thereof,wherein A is C₁-C₁₀ heteroaryl optionally substituted by at least oneselected from the group consisting of halo, chlorophenyl, C₁-C₆ alkyl,C₃-C₇ cycloalkyl, C₆-C₁₂ aralkyl, C₁-C₆ alkoxy, and C₆-C₁₂ aryl; and Bis O or NH.
 9. The method of claim 8, wherein the cognitive disorder isselected from the group consisting of pre-senile dementia, early onsetAlzheimer's disease, senile dementia, Lewy body corpuscle dementia,micro-infarct dementia, AIDS-related dementia, HIV-dementia, dementiaassociated with Lewy bodies, Down's syndrome associated dementia, Pick'sdisease, mild cognitive impairment, recent short-term memory impairment,age-associated cognitive disorder, drug-associated cognitive disorder,immunodeficiency syndrome-associated cognitive disorder, vasculardisease-associated cognitive impairment and learning deficit disorder.10. The method of claim 8, wherein B is NH.
 11. The method of claim 8,wherein A is thiazolyl, benzothiazolyl, pyridyl, isoxazolyl,isoquinolinyl, quinolyl, benzothiadiazolyl, thiadiazolyl, pyrazolyl orpyrazinyl, which is optionally substituted by at least one selected fromthe group consisting of halo, chlorophenyl, C₁-C₆ alkyl, C₃-C₇cycloalkyl, C₆-C₁₂ aralkyl, C₁-C₆ alkoxy, and C₆-C₁₂ aryl.
 12. Themethod of claim 8, wherein A is thiazolyl or benzothiazolyl optionallysubstituted by at least one selected from the group consisting of halo,chlorophenyl, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₆-C₁₂ aralkyl, C₁-C₆alkoxy, and C₆-C₁₂ aryl.
 13. The method of claim 8, wherein A is C₁-C₁₀heteroaryl substituted by at least one selected from the groupconsisting of chloro, methyl, ethyl, propyl, iso-propyl, tert-butyl,cyclopentyl, phenyl, chlorophenyl, benzyl, cyclohexyl and methoxy. 14.The method of claim 8, wherein A is selected from thiazolyl,methylthiazolyl, ethylthiazolyl, propylthiazolyl, iso-propylthiazolyl,tert-butylthiazolyl, cyclopentylthiazolyl, cyclohexylthiazolyl,phenylthiazolyl, chlorophenylthiazolyl, benzylthiazolyl, chlorothiazolyland dimethylthiazolyl.
 15. The method of claim 14, wherein B is NH. 16.The method of claim 8, wherein the compound is selected from the groupconsisting of:N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-thiazolyl)-3-pyridinecarboxamide,N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-6-oxo-1-(2-thiazolyl)-3-pyridinecarboxamide,N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-oxo-1-(2-thiazolyl)-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-pyridinyl)-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(3-pyridinyl)-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-chloro-2-pyridinyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-phenyl-2-pyridine-1-yl)-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(3-isoxazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(3-phenyl-5-isoxazolyl)-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-methyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-methyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-methyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-ethyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-ethyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-ethyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-propyl-2-thiazolyl)-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-propan-2-yl-2-thiazolyl)-3-pyridinecarboxamide,N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-6-oxo-1-(5-propan-2-yl-2-thiazolyl)-3-pyridinecarboxamide,N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-6-oxo-1-(5-propan-2-yl-2-thiazolyl)-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-tert-butyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl)]-1-(5-tert-butyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl)]-1-(5-tert-butyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-cyclopentyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-cyclohexyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-phenyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-chloro-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-chloro-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-chloro-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-[5-(phenylmethyl)-2-thiazolyl]-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-methyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-(4-chlorophenyl)-2-thiazolyl]-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4,5-dimethyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(1,3-benzothiazole-2-yl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-methoxy-1,3-benzothiazole-2-yl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5,6-dimethyl-1,3-benzothiazole-2-yl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(2,1,3-benzothiadiazole-4-yl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(1,3-benzothiazole-6-yl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-methyl-2-phenyl-3-pyrazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(1-isoquinolinyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-isoquinolinyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-quinolinyl)-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-methyl-1,3,4-thiadiazole-2-yl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-phenyl-1,3,4-thiadiazole-2-yl)-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-pyrazinyl)-3-pyridinecarboxamide,(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-methyl-1,3-thiazole-2-yl)-6-oxo-3-pyridinecarboxylate,and(2-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-propan-2-yl-1,3-thiazole-2-yl)-3-pyridinecarboxylate.17. The method of claim 8, wherein the compound is selected from thegroup consisting of:N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-thiazolyl)-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-methyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-ethyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-propyl-2-thiazolyl)-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-propan-2-yl-2-thiazolyl)-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-tert-butyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-cyclopentyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-cyclohexyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-phenyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-chloro-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-[5-(phenylmethyl)-2-thiazolyl)]-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-methyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-[4-(4-chlorophenyl)-2-thiazolyl]-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4,5-dimethyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(1,3-benzothiazole-2-yl)-6-oxo-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(4-methoxy-1,3-benzothiazole-2-yl)-6-oxo-3-pyridinecarboxamide,andN-(1-azabicyclo[2.2.2]octan-3-yl)-1-[5,6-dimethyl-1,3-benzothiazole-2-yl)-6-oxo-3-pyridinecarboxamide.18. The method of claim 8, wherein the compound is selected from thegroup consisting of:N-(1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-thiazolyl)-3-pyridinecarboxamide,N-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-methyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,andN-(1-azabicyclo[2.2.2]octan-3-yl)-1-(5-ethyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide.19. The method of claim 8, wherein the compound is selected from thegroup consisting of:N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(2-thiazolyl)-3-pyridinecarboxamide,N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-methyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-methyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-ethyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-ethyl-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-propan-2-yl-2-thiazolyl)-3-pyridinecarboxamide,N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl)-6-oxo-1-(5-propan-2-yl-2-thiazolyl)-3-pyridinecarboxamide,N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-[5-tert-butyl-2-thiazolyl]-6-oxo-3-pyridinecarboxamide,N-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-[5-tert-butyl-2-thiazolyl]-6-oxo-3-pyridinecarboxamide,N-[(3R)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-chloro-2-thiazolyl)-6-oxo-3-pyridinecarboxamide,andN-[(3S)-1-azabicyclo[2.2.2]octan-3-yl]-1-(5-chloro-2-thiazolyl)-6-oxo-3-pyridinecarboxamide.20. The method of claim 8, wherein the method comprises administrationof the compound in a form of a pharmaceutical composition which furthercomprises a pharmaceutically acceptable carrier.
 21. The method of claim20, wherein the pharmaceutical composition is an oral formulation.